Neural stem cell-derived small extracellular vesicles attenuate apoptosis and neuroinflammation after traumatic spinal cord injury by activating autophagy

Abstract

Spinal cord injury (SCI) can cause severe irreversible motor dysfunction and even death. Neural stem cell (NSC) transplantation can promote functional recovery after acute SCI in experimental animals, but numerous issues, including low-transplanted cell survival rate, cell de-differentiation, and tumor formation need to be resolved before routine clinical application is feasible. Recent studies have shown that transplanted stem cells facilitate regeneration through release of paracrine factors. Small extracellular vesicles (sEVs), the smallest known membrane-bound nanovesicles, are involved in complex intercellular communication systems and are an important vehicle for paracrine delivery of therapeutic agents. However, the application of NSC-derived small extracellular vesicles (NSC-sEVs) to SCI treatment has not been reported. We demonstrate that NSC-sEVs can significantly reduce the extent of SCI, improve functional recovery, and reduce neuronal apoptosis, microglia activation, and neuroinflammation in rats. Furthermore, our study suggests that NSC-sEVs can regulate apoptosis and inflammatory processes by inducing autophagy. In brief, NSC-sEVs increased the expression of the autophagy marker proteins LC3B and beclin-1, and promoted autophagosome formation. Following NSC-sEV infusion, the SCI area was significantly reduced, and the expression levels of the proapoptotic protein Bax, the apoptosis effector cleaved caspase-3, and the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were significantly reduced, whereas the expression level of the anti-apoptotic protein Bcl-2 was upregulated. In the presence of the autophagy inhibitor 3MA, however, these inhibitory effects of NSC-sEVs on apoptosis and neuroinflammation were significantly reversed. Our results show for the first time that NSC-sEV treatment has the potential to reduce neuronal apoptosis, inhibit neuroinflammation, and promote functional recovery in SCI model rats at an early stage by promoting autophagy.

<p>Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Improves Spinal Cord Function After Injury in Rats by Activating Autophagy</p>

“…Recent studies show that autophagy influences the recovery of motor function following SCI. 25,26 It is also involved in numerous neurodegenerative illnesses as well as in ischemic and traumatic brain damage. 27 Several studies show that autophagy is essential to the regulation of cell homeostasis as it acts as a quality control process for cellular biomolecules.…”

Effects of neural stem cell‐derived extracellular vesicles on neuronal protection and functional recovery in the rat model of middle cerebral artery occlusion

“…Severe neuronal apoptosis is an outcome of stroke, especially in aged animals . Roles for NSC‐EVs on augmenting the ratio for neuronal survival/apoptosis is reported so far for Parkinson and spinal cord injury (SCI), and the results were promising. Combining with our findings, we could assert that NSC‐EVs‐based intervention is capable of protecting neurons threatened by brain ischemia.…”

Exosome-shuttled miR-216a-5p from hypoxic preconditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization

“…[35][36][37][38]. Our studies have shown that exosomes derived from MSCs could enhance functional recovery after SCI by inhibiting neuroinflammation and promoting axonal regeneration [39,40]. A clinical trial was developed to evaluate the effects of MSC-derived exosomes on the possible treatment of type I diabetes mellitus (Clini-calTrials.gov, NCT02138331) and the first patient has successfully been treated with MSC exosomes in graft versus host disease [41].…”